The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2

Abstract

To determine whether CCL2 mRNA expression is beneficial or detrimental for cervical cancer patients, the association between the expression of this molecule by cervical tumour cells, the number of tumour‐associated macrophages, and clinicopathological parameters such as recurrence, relapse‐free survival, and overall patient survival was investigated. In cervical cancer samples from 93 untreated cervical cancer patients, the CCL2 mRNA expression level was quantified using RNA in situ hybridization and verified using real‐time quantitative RT‐PCR. The number of tumour‐associated macrophages was determined using immunohistochemistry. Furthermore, the study investigated whether lack of CCL2 expression was due to genetic alterations near the 17q11.2 (CCL2 genomic) region. CCL2 mRNA expression by cervical tumour cells was associated with the number of tumour‐associated macrophages (p < 0.001). Lack of CCL2 mRNA expression (15 samples; 16%) was associated with increased cumulative relapse‐free survival (log rank test, p = 0.030), increased cumulative overall survival (log rank test, p = 0.024), less post‐operative surgery, reduced local and distant recurrence, reduced vascular invasion, and smaller tumour size (<40 mm). The absence of CCL2 mRNA expression corresponded with loss of heterozygosity (LOH) at 17q11.2 in five of six samples. The increased cumulative relapse‐free survival and cumulative overall survival of cervical cancer patients lacking tumour cell‐associated CCL2 mRNA suggest that the tumour‐associated macrophages support tumour progression, presumably by promoting angiogenesis and production of growth factors. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Role of tumor‐derived proinflammatory cytokines GM‐CSF, TNF‐α, and IL‐12 in the migration and differentiation of antigen‐presenting cells in cervical carcinoma

“…11,14 We have shown that expression of CCL2 (MCP-1) by the cervical cancer cells is associated with an increased number of macrophages and a decreased disease-free survival of cervical carcinoma patients. 15 Furthermore, we have observed a down-regulation of the expression level of proinflammatory cytokines such as GM-CSF, TNF-a, and IL-12 in cervical carcinoma cell lines. 12 GM-CSF, TNF-a, and IL-12 are important in profiling immune reactivity.…”

“…28 We have previously shown that CCL2 expressed by cervical tumor cells is associated with the presence of TAM at the tumor site. 15 In addition to CCL2, TNF-a expression is often correlated with large numbers of inflammatory cells. 8,29 Indeed, a positive association between TNF-a expression and stromal TAM was found.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…However, these chemokines are usually associated with pro-rather than anti-tumor activities. For example, CCL2 (MCP-1), which is overexpressed in a wide range of cancers [234], is associated with poor prognosis in breast, colorectal, cervical and thyroid cancers [235][236][237][238][239]. Tumor-derived CCL2 plays a pro-tumor role by recruiting inflammatory monocytes to pulmonary metastases [240] and MDSCs to the tumor microenvironment [241], as well as promoting angiogenesis [242], tumor cell proliferation [243] and migration [244].…”

Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer

“…Probes were prepared and cervical carcinoma sections were stained for versican mRNA as previously described. 28 In short, 3 mm paraffin sections were pre-treated and hybridized with 100 ng/ml digoxigenin-labeled mRNA probe diluted in hybridization mixture containing 0.3 M NaCl and 0.03 M saline sodium citrate (SSC). Hybridization was allowed for 16 h at 55 1C in a humidified chamber.…”